title: Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2.
abstract: BACKGROUND
  This phase 1 study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, cerebrospinal fluid (CSF) distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285.
  
  
  METHODS
  Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status ≤2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose (RP2D) were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors.
  
  
  RESULTS
  Fifty-four patients were enrolled (median age 60; range, 35-76 years). The most common diagnoses were cancers of the colon (28 %), breast (17 %), and pancreas (9 %). Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD/RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast (median time of maximum concentration was 2-3 h), and mean half-life was 9 h. Steady-state average unbound CSF concentration (geometric mean 1.54 [range, 0.51-4.27] ng/mL; n = 5) at the RP2D was below the 50 % inhibitory concentration (9.3 ng/mL) for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease (12 weeks of nonprogression) in 13 patients.
  
  
  CONCLUSIONS
  TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition.
authors.affiliation: Karmanos Cancer Institute, Wayne State University, 4100 John R St., Detroit, MI, 48201, USA, lorussop@karmanos.org.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Dennis
authors.initials: D
authors.lastname: Noe
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Serap
authors.initials: S
authors.lastname: Sankoh
authors.forename: Maria
authors.initials: M
authors.lastname: Corvez
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003710:Demography; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D006885:Hydroxybutyrates / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D066246:ErbB Receptors; D006885:Hydroxybutyrates; D018719:Erb-b2 Receptor Tyrosine Kinases; C570404:N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide